Carbacyclin induces CPT-1 in cardiac myocytes via PPARδ, independent of the IP receptor signaling pathway

Abstract

Prostacyclin (PGI2) has been reported to exert cardioprotective effects via the rhodopsin type PGI2 receptor, IP. Recently, a second signaling pathway of PGI2 via peroxisome proliferator-activated receptor (PPAR) δ, was demonstrated. PPARδ exerts a pivotal role in maintaining constitutive myocardial fatty acid β oxidation (FAO).The objective of this study was to examine whether carbacyclin (cPGI2), a PGI2 analogue, up-regulates transcriptional expression of carnitine palmitoyl-transferase-1 (CPT-1), the rate-limiting enzyme in mitochondrial FAO, via PPARδ in cardiomyocytes. CPT-1 mRNA expression in the cardiac tissue was enhanced in mice injected with 100 μg cPGI2. Transcriptional activity was evaluated by PPAR responsive element (PPRE)-luciferase reporter gene assay in cultured neonatal rat cardiomyocytes. CPT-1 mRNA expression and PPRE promoter activity were significantly increased by cPGI2 in a dose-dependent manner, w here PPRE has been known to be mapped in the CPT-1 promoter region. cPGI2 also induced a dose-dependent phosphorylation of CREB indicating activation of the IP signaling pathway. Moreover, the elevated CPT-1 mRNA expression and PPRE promoter activity by cPGI2 were not abolished by inhibition of the IP receptor signaling pathway, but were significantly attenuated in cardiomyocytes transfected with a dominant negative form of PPARδ utilizing adenovirus vectors, indicating that cPGI2 induces CPT-1 mRNA expression through PPARδ in cardiomyocytes. These results suggest that cPGI2 might modulate cardiac energy metabolism by activating FAO via PPARδ, independent of the IP receptor signaling pathway.